Massive Transfusion in 30 minutes or less

18 Oct 2010

Kate Chipperfield MD FRCPCVancouver Coastal Health

University of British Columbia

Objectives

1. Definitions of MT2. Complications of MT3. VCH protocol for MT, and planned TEP4. MTP’s and 1:1 blood product ratios5. rfVIIa (Niastase™)6. Antifibrinolytics in Trauma

Definition of MT

Commonly used definition: 10 or more units of PRBC given within a 24-

hour period.

Retrospective - needs a more dynamic definition:

6+ units in one bleeding episode with ongoing losses

4+ units in one hour with ongoing losses replacement 50% BV in 3 hours rate of loss ≥ 150 ml/min etc…

Types of patients

What types of patients are likely to require MT?

Blunt or penetrating trauma Cardiovascular surgery/ruptured AAA Massive GI bleeds Catastrophic obstetrical events Previously unrecognized bleeding diathesis Liver transplant Other

Physician M’ment of MT Event

Flow diagram (VA and RH)

RN and Technologist procedures

If you inform the blood bank of a MT, they will call Hematology lab to ensure ‘stat’ lab tests, and start thawing plasma

Cochrane Collaboration 2007 review of 55 RCTs; crystalloid vs colloid in resuscitation- no difference in survival- colloids are more expensive with no apparent benefit

‘Transfusion triggers’

Blood product administration should be guided by clinical bleeding AND labs:

RBCs to maintain Hb > 80; set goal as 100g/L

Plasma aim for INR and/or PTT < 1.5 x normal±Cryo to maintain fibrinogen > 1.0 g/L

Plts maintain > 50-80; set goal >80 or > 100 if CNS/multi-trauma Exception – if plts dysfunctional then count not

helpful (e.g. CPB, anti-plt meds, uremia)

e.g. antifibrinolytics

Does cryo have a role in MT?

Plasma Volume 200 -250 ml 1 dose = 3-4 units All coag factors

Fibrinogen 500 mg/unit

Cryoprecipitate Volume 10 ml per unit 1 dose = pool of 10

units FVIII, vWF, FXIII and…

Fibrinogen > 1.5 g/pool

Therefore 1 dose of plasma has at least as much fibrinogen as 1 dose of cryo. Cryo more useful in situations requiring fibrinogen in small volume.

Selecting red cells, and Switching Groups

Emergency Group O red cells Reserve Rh neg units for children and

women of child-bearing age (CSA Standard)

We can issue group-specific RBCs within minutes, once we have rec’d the pt sample. It does not matter how many group O units the pt may have received. Remaining plasma in one RBC unit is ~15 ml

Complications of MT

1. Hypothermia

2. Citrate toxicity

3. Increased risk of transfusion errors

4. Metabolic - altered K+ and pH; 2,3-DPG

5. Impaired hemostasis - multifactorial

6. Transfusion Reaction (s)

Avoiding the vicious cycle:

A ‘stat’ INR/PTT may take >1 hour

Do we lose valuable time if we wait to transfuse plasma before labs are back?

‘Acute coagulopathy of trauma’ – suggestion that trauma pts who present with prolonged coags have higher mortality

Hemorrhage

Hemodilution HypothermiaAcidosis

Coagulopathy

Coagulopathy: Elective surgery vs trauma setting

What about a formulaic approach to MT?

Some centres in US advocate a MT package of blood product e.g. 1:1 RBC/plasma e.g. 6:4:1 RBC/plasma/platelets

Historical context: 1970s: military/trauma approach to hemorrhagic

shock was large volumes crystalloid + whole blood 1980s: Move away from WB to blood components –

patients got crystalloid + PRBCs Recognition of inadvertent hemodilution, respiratory

distress, and compartment syndrome

AB Plasma Units Shipped to Hospitals by Month

750

950

1,150

1,350

1,550

1,750

1,950

2006

/Jan

2006

/Mar

2006

/May

2006

/Jul

2006

/Sep

2006

/Nov

2007

/Jan

2007

/Mar

2007

/May

2007

/Jul

2007

/Sep

2007

/Nov

2008

/Jan

2008

/Mar

2008

/May

2008

/Jul

2008

/Sep

2008

/Nov

2009

/Jan

2009

/Mar

50% increase

PublicationsOn 1:1

Issues of AB plasma by month for the last 4 years in Canada

Retrospective chart review of 246 pts who had MT in Iraq.

Pts grouped by the ratio of plasma to RBCs they received during their MT.

Authors’ conclusions: “..MT protocols should utilize a 1:1 ratio of plasma to RBCs for all patients who are hypocoagulable with traumatic injuries.”

Limitations:- Retrospective, some data not retrievable or inaccurate- No standardized MT protocol- Used whole blood and non-leukoreduced products- Mostly young men (median age 24; only 3 female)- 94% were penetrating injuries- Differences in baseline characteristics between groups- Low ratio group included patients who died before plasma could be thawed

Many Many other publications … Civilian trauma studies

Duchesne JC et al, J Trauma 2008, 65:272-276 Retrospective review of both non-massive and

massive transfusion In MT, mortality 87.5% (less plasma) vs 26% (more

plasma)

Scalea TM et al, Ann Surg 2008, 248:578-584 Prospective observational study of trauma patients The plasma to red cell ratio did not predict survival or

LOS in ICU or hospital in either MT or non-MT

Survivorship bias

Snyder et al, J Trauma 66:358-364, 2009 The authors sought to control for survivorship

bias by controlling for the timing of FFP retrospective cohort study of 134 trauma

patients who received ≥10 RBC in 24h In their centre, plasma is not kept thawed Divided patients into low ratio (<1:2) and high

ratio (≥1:2) groups at varying time points: (every 30 mins for the first 2 h, hourly from 2-6 h,

and every 6 h until 24 h)

Snyder et al, J Trauma 66:358-364, 2009

Median time to the first RBC was 18 min, and first FFP was 93 minutes The start times for the first FFP ranged from 24 to 350

minutes!

Key Finding:

Over time, patients moved from low-ratio to high-ratio group at 90 min: 83% low-ratio; at 6 h: 53% low-ratio Among early deaths, more occurred in the low-ratio

group Among late deaths, more occurred in the high-ratio

group

Snyder et al, J Trauma 66:358-364, 2009

Snyder et al, J Trauma 66:358-364, 2009

“As component blood products are not administered uniformly and simultaneously in civilian clinical practice, and many deaths occur early, it is possible that the survival advantage observed among those receiving a higher FFP:PRBC ratio may simply reflect the fact that they lived long enough to receive the higher ratio of products.”

One question this study doesn’t address is the effect of having thawed plasma ready and available

But is it feasible for Canada to have thawed AB plasma available at all times? Thawed plasma can be stored for 24 h in the fridge;

cannot be refrozen (in US they can keep thawed plasma for 5 days)

Much AB plasma in Canada still comes from female donors, therefore at increased risk of causing TRALI

0

10

20

30

40

50

60

70

80

90

100

O A B AB

Male

Female

Percentage of Male vs Female plasma produced by CBS by blood group

J Am Coll Surg

One Size does not fit all!Retrospective, NonMT Trauma, 1716 pts,

Excluded early deaths

Final thoughts on “1:1”

In general, the concept of plasma earlier rather than later for coagulopathic trauma patients is supported

No good evidence (yet) to suggest the optimal timing or ratio of FFP to RBC

Hospital should develop own MT protocol taking into account patient pop and resources

We will likely never have thawed AB plasma available 24/7 so order plasma early knowing that there will be >30 min delay for thawing

Platelets are suspended in plasma!

VGH, Future Trauma Exsanguination Protocol (TEP) In general, the concept of plasma earlier

rather than later for coagulopathic trauma patients is supported VGH developing TEP – 2011 Criteria include: 4uRBC in and ongoing rapid Tx needs PLUS;

Poor hemodynamic response and SBP <90 mmHg

Base Deficit < -8 pH <7.25

rFVIIa (Niastase)

Developed as a ‘bypassing agent’ for Hemophilia A and B patients with Inhibitors (antibodies to factor) These pts no longer respond to simple factor

replacement therapy

Canada: Any use outside of Hemophilia is OFF LABEL

In some countries it is also licensed for: Congenital factor VII deficiency Glanzmann’s thrombasthenia where plt transfusions

ineffective

The Coagulation Cascade

Exogenous FVIIabypasses the problem in hemophiliacs

Cell-Based Model of Hemostasis (Hoffman): Where does Niastase Come In?

VIIIIX

vWF

Is there any evidence that rFVIIa works in MT? Lots of personal anecdotal reports and case studies

? Literature bias against negative studies

Limited number of RCTs in various bleeding situations Some have shown small reduction in units transfused

but no evidence of improved outcomes

What is the risk of giving it? Several RCTs have shown small increased risk of

thrombosis (dose dependent) COST

(trauma, ICH, liver transplant, cardiac surgery, prostatectomy, SCT)Conclusions:- most are dose-finding studies that are powered to find reductions in units transfused, not reduced morbidity/mortality- studies are too small to adequately assess risk of thromboembolism- high risk pts usually excluded from studies (age >65, DIC/sepsis, Hx of thrombosis, mechanical heart valve, etc)

2008: National Advisory Committee (NAC) reviewed published RCTs re use of rFVIIa in various bleeding scenarios.

NAC recommendations

The current evidence does not support the routine use of rFVIIa in MT However its use should be part of a MT framework for

use on a case-by-case basis

Consider when: Massive intractable bleeding (>8 units in 24h or >4

units in first hour with ongoing bleeding) AND all other measures to achieve hemostasis have

been attempted

Dose: 20-50 g/kg and round to nearest vial Repeat at 30 min and up to 2h (max 3 doses)

Niastase – Cost and Access (VA)

~$1000 per mg 1.2mg, 2.4mg and 4.8mg vials (changing to 1mg, 2mg, 5mg)

Call Blood Bank (54420) to order – hematopathologist approval

For faster approval have recent coags, pH, temperature and pt weight available to discuss with HP

There must be adequate platelets and reasonable coagulation profile

Acidosis and hypothermia must be corrected

Surgical bleeding must be excluded

rFVIIa is not explicitly stated but would go here

VGH MT protocol….

Antifibrinolytics in MT?

CRASH-2 trial (Lancet 2010: 376:23-32) RCT of 20,211 adult trauma patients in 274 hospitals

in 40 countries Randomized to receive placebo or

TXA 1 g over 10 min then infusion 1 g over 8h Treatment initiated within 8 hours of injury Staff blinded to treatment arm

Results: All cause mortality sig reduced in TXA arm (14.5% vs

16.0%) Death due to bleeding sig reduced in TXA arm (4.9% vs

5.7%) Vascular occlusive events did not differ (1.7% vs 2.0%) Blood transfusion rate not different (50.4% vs 51.3%)

How did TXA reduce mortality? Suppression of plasmin

proinflammatory effects?

Questions about Massive Transfusion? VCH TM Intranet site:http://vchconnect/programs_services/transfusion_medicine/

page_29666.htm

References

Stanworth et al. Recombinant fVIIa for the prevention and treatment of bleeding in patients without hemophilia. Cochrane Database of Systematic Reviews 2007, Issue 2. April 18.

Mathew, P et al. How we manage requests for rfVIIa. Transfusion 2007;47:8-14.

Boffard K et al. Recombinant fVIIa as adjunctive threapy for bleeding control in severely injured Trauma Patients: Two parallel randomized, placebo-controlled, double blind clinical trials. Journal of Trauma 2005 59 (1)8-18.

Webert et al.Letters to the Editor. Journal of Trauma 2006;60(1):242-3.

Teixeira et al, Impact of plasma transfusion in massively transfused trauma patients. J Trauma 66:693-697, 2009

Link, K et al. A high ratio of plasma and platelets to packed red blood cells in the first 6 hours of massive transfusion improves outcomes in a large multicenter study. Am J Surg 197, 565-570, 2009

Snyder, CW et al, The relationship of blood product ratio to mortality: survival benefit or survival bias. J Trauma 66:358-364, 2009

CRASH-2 trial (Lancet 2010: 376:23-32)

Other references: See Physician Management of Massive Transfusion Event, VCH TM Intranet site